Is SPEG p.Pro2827= (c.8481T>A) pathogenic?

SPEG p.Pro2827= (c.8481T>A) is classified Likely benign in SPEG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-02). Very rare (popmax 0.00691%, nfe).

How common is SPEG p.Pro2827= (c.8481T>A) in the general population?

SPEG p.Pro2827= (c.8481T>A) is very rare (popmax 0.00691%, nfe) (gnomAD).

SPEG p.Pro2827=

c.8481T>A · rs745952268 · VCV2162301

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00691%, nfe)

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -0.16	GERP -0.89
Overall
CADD	0.947	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00691% European (non-Finnish) · 67/970,054 alleles

Filtering AF 0.00552% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00507%

Overall 0.00556% 71/1,277,336 alleles · very rare exomes 66/1,221,398 · genomes 5/55,938 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00691%	14,478
Remaining individualsnot grpmax-eligible	0.00421%	23,756
African / African-American	0.0024%	41,660
Admixed American	0.00233%	42,986

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SPEG
Protein: p.Pro2827=
Coding: c.8481T>A
MANE Select: NM_005876
dbSNP: rs745952268
Type: single nucleotide variant
Location: chr2:219489499 (GRCh38)

Full SPEG gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/speg-p-pro2827 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown